Link between GIP and osteopontin in adipose tissue and insulin resistance - PubMed (original) (raw)

. 2013 Jun;62(6):2088-94.

doi: 10.2337/db12-0976. Epub 2013 Jan 24.

Peter Osmark, Tiina Kuulasmaa, Kasper Pilgaard, Bilal Omar, Charlotte Brøns, Olga Kotova, Anna V Zetterqvist, Alena Stancáková, Anna Jonsson, Ola Hansson, Johanna Kuusisto, Timothy J Kieffer, Tiinamaija Tuomi, Bo Isomaa, Sten Madsbad, Maria F Gomez, Pernille Poulsen, Markku Laakso, Eva Degerman, Jussi Pihlajamäki, Nils Wierup, Allan Vaag, Leif Groop, Valeriya Lyssenko

Affiliations

Emma Ahlqvist et al. Diabetes. 2013 Jun.

Abstract

Low-grade inflammation in obesity is associated with accumulation of the macrophage-derived cytokine osteopontin (OPN) in adipose tissue and induction of local as well as systemic insulin resistance. Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13 ± 0.04 vs. 0.04 ± 0.01, P < 0.05) and correlated inversely with measures of insulin sensitivity (r = -0.24, P = 0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with a lower amount of the exon 9-containing isoform required for transmembrane activity. Carriers of the A allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of the GIPR rs10423928 A allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.

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Figures

FIG. 1.

FIG. 1.

Expression of the GIPR in adipose tissue. A: Immunostainings demonstrating that GIPR (green) is abundantly expressed in human, mouse, and rat white adipose tissue (top) and skeletal muscle (bottom). Scale bar, 50 µm. B: Agarose gel electrophoresis of RT-PCR across the variable part of GIPR cDNA (from exon 2 to 10) from SAT and VAT samples from seven individuals. The size of the predicted functional GIPR amplicon of 887 bp is indicated, as well as the size range of identified splice variants (green bars). C: Schematic representation of alternative splicing of the full-length GIPR. Black exons are obligatory and colored are variable. Dashed lines indicate rare events. Exon 1, which is noncoding, is presumably variable. Exons 3 and 5 possess alternative splice sites. The GIP binding site (HormR) and the transmembrane domain (7tm_2) are indicated. Transmembrane helices (gray) I, II, III, and VI are encoded by single exons. Splice variants were detected by RT-PCR and sequencing. Variants predicted to yield a fully functional membrane-bound GIPR are indicated by asterisks. D: Proportion of full mRNA splice variants including exon 9 is decreased in the adipose tissue of subjects with the A allele of rs10423928 (ANOVA, P < 0.05). PCR primers are shown in exons 8 and 11. Variant ratios were detected using PCR and capillary electrophoresis. Peak areas were used to calculate the relative quantities of the PCR products.

FIG. 2.

FIG. 2.

Effects of GIP and GIPR genotype on OPN expression in adipocytes. A: Correlation between OPN mRNA in adipose tissue and ISI in different GIPR SNP rs10423928 carriers (Danish Twins Study, n = 83) (TT, black solid lines and gray circles; TA/AA, dashed lines and empty circles). B: Expression of OPN mRNA was lower in adipose tissue from TA/AA vs. TT genotype carriers (Danish Twins Study, *P < 0.05). C: GIP stimulation induces OPN in primary rat adipocytes. Adipocytes were isolated from rat epididymal fat pads and incubated overnight (∼18 h) in media containing either 5 or 25 mmol/L glucose in the presence of GIP and insulin at the indicated concentrations. Data are presented as mean ± SEM of OPN protein expression relative to β-actin, expressed as percent of control cell (25 mmol/L glucose) expression. n = 6–12 per condition. *P < 0.05; **P < 0.01; ***P < 0.001.

FIG. 3.

FIG. 3.

Diagram of the design and summary of the study. DEXA, dual-energy X-ray absorptiometry. P-GIP, plasma-GIP.

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